The human disease, Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV), particularly the strain known as HIV-1.
Like other viruses, HIV-1 cannot replicate without commandeering the biosynthetic apparatus of the host cell it infects. It causes this apparatus to produce the structural proteins which make up the viral progeny. These proteins are coded for by the genetic material contained within the infecting virus particle, or virion. Being a retrovirus, however, the genetic material of HIV is RNA, not DNA as in the host cell's genome. Accordingly, the viral RNA must first be converted into DNA, and then integrated into the host cell's genome, in order for the host cell to produce the required viral proteins. The conversion of the RNA to DNA is accomplished through the use of the enzyme reverse transcriptase (RT), which is included within the infecting virion along with the RNA. Reverse transcriptase has three known enzymatic functions; it acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting first as an RNA-dependent DNA polymerase, RT makes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT frees the DNA just produced from the original viral RNA and destroys the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by another enzyme called integrase.
Compounds which inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells.
A number of compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase are known. One class of known HIV-1 RT inhibitors is the nucleoside analogs. This class includes 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxy-cytidine (ddC). Another class is the non-nucleoside analogs. This class includes, inter alia, nevirapine, which is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido3,2-b:2',3'-e!1,4!-diaze pin-6-one. Nevirapine and other paricularly relevant compounds of the non-nucleoside class are described in U.S. Pat. No. 5,366,972; by Hargrave et al.,"Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 1. Tricyclic Pyridobenzo-and Dipyridodiazepinones", J. Med. Chem., 34, 2231 (1991); and by Proudfoot et al., "Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 4.2-Substituted Dipyridodiazepinones are Potent Inhibitors of both Wild Type and Cysteine-181 HIV-1 Reverse Transcriptase Enzymes". J. Med. Chem., 38, 4830-4838 (1995).